This proposal is designed to provide John Hartman with the scientific expertise and career development for success in academic medicine and basic science. Dr. Hartman has completed the clinical year of his hematology fellowship at the University of Washington, and is in the second year of research fellowship at the Fred Hutchinson Cancer Research Center under guidance of his mentors, Lee Hartwell and Maynard Olson. During the next five years, Dr. Hartman plans to continue his studies of molecular buffering of the DNA replication apparatus in yeast. By these studies, Dr. Hartman aims to gain new insights into the initiating events in cancer. He will employ novel methodologies for genome-wide analysis in yeast to understand in more detail the molecular pathways that maintain replication fidelity, with a special focus on the impact of genetic variation on these pathways. Dr. Hartman will undertake coursework related to cancer biology and analysis of complex biologic traits to further attain his scientific research goals. FHCRC has many faculty members with shared interests, who are engaged in related studies. Accordingly, an advisory board has been assembled to facilitate Dr. Hartman's research and academic progress. Dr. Hartman's long-term career goal is to better understand human genetic diversity as it relates to health and disease, which is one of the initiatives of the human genome project. The research tools necessary to begin analyzing such biologic complexity are presently available and under rapid development. A global appreciation of the interplay between genetic variation and molecular homeostasis is fundamental to understanding the genetic architecture of complex traits, such as cancer. This proposal is to use, in combination, tetracycline-regulated gene expression and the set of over 4000 haploid yeast deletion strains to comprehensively and systematically identify all non- essential genes capable of buffering replication stress. Such a detailed analysis is currently possible only in isogenic yeast, but it will provide the scientific foundation to investigate the impact of naturally occurring genetic variation upon replication fidelity in humans. During the five years of this research, Dr. Hartman will gain insight into molecular principles of cellular homeostasis, as they relate to replication fidelity and cancer, and he will develop aptitude for genome analysis that will serve him well throughout his career as an independent research scientist.